Stapled β-Hairpins Featuring 4-Mercaptoproline

J Am Chem Soc. 2021 Sep 22;143(37):15039-15044. doi: 10.1021/jacs.1c04378. Epub 2021 Sep 13.

Abstract

Peptides constrained by intramolecular cross-links, especially stapled α-helices, have emerged as versatile scaffolds for drug development. However, there are fewer examples of similarly constrained scaffolds for other secondary structures. Here, we used a novel computational strategy to identify an optimal staple for antiparallel β-strands, and then we incorporated that staple within a β-hairpin peptide. The hairpin uses 4-mercaptoproline as a novel staple component, which contributes to a unique, kinked structure. The stapled hairpins show a high degree of structure in aqueous solution, excellent resistance to degradation in cell lysates, and cytosolic penetration at micromolar concentrations. They also overlay with a unique subset of kinked hairpin motifs at protein-protein interaction interfaces. Thus, these scaffolds represent promising starting points for developing inhibitors of cellular protein-protein interactions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Models, Molecular
  • Peptides / chemical synthesis*
  • Peptides / chemistry
  • Proline / analogs & derivatives*
  • Proline / chemistry
  • Protein Structure, Secondary

Substances

  • 4-mercaptoproline
  • Peptides
  • Proline